Table 2.
Experimental animal model supporting the role of the gut microbiota in hepatocarcinogenesis.
| Ref. no. | Animal model | Carcinogenetic agent | Intervention | Results |
|---|---|---|---|---|
| 58 | Rat (Sprague-Dawley) Mice (C57BL/6; TLR–/–) | DEN | - Gut sterilization by antibiotic treatment | Tumor incidence and growth were reduced |
| 38 | Mice (C3H/HeN; C57BL/6 FL-N/35) | AFB-1 | - H. hepaticus intestinal colonization in AFB-1 model - H. hepaticus intestinal colonization in HCV transgenic mice | The co-administration of H. hepaticus with AFB-1 lead to greater tumor number and size in comparison to AFB-1 alone The combination of HCV transgene expression and H. hepaticus infection lead to liver tumor |
| 39 | Rat (Sprague-Dawley) | DEN | - Penicillin or DSS-induced dysbiosis - Probiotic administration - 16S rRNA PCR for microbial analysis | Chronic DEN treatment was associated with reduced levels of Lactobacillus spp., Bifidobacterium spp. and Enterococcus spp. Dysbiosis promoted liver carcinogenesis Probiotics decreased liver tumor number and size |
| 36 | Mice (C3H/HeOuJ; C3H/HeJ; C57BI/6; TLR2–/–; TLR4–/–; TNFR1–/–-IL-1R1–/–) | DEN+CCL4 DEN+CD | - LPS continuous administration in WT DEN/CCL4 mice - Germ-free mice or gut sterilization by antibiotic treatment | LPS increased tumor number and size Tumor number and size were reduced in gut sterilized or germ-free WT DEN/CCL4 mice TLR4 depletion had no effect on tumor incidence but decreased HCC tumor number and size |
| 44 | Mice (C57BL/6; Il-1β–/–; TLR4–/–; CD1; ob/ob) | DMBA | - DMBA+HFD - Gut sterilization by antibiotic treatment - DCA serum levels quantification - DCA oral administration - 16S rRNA PCR for microbial analysis | Dietary and genetically obese mice treated with DMBA developed HCC and showed increased levels of serum DCA DCA oral administration in lean mice fed a normal diet increased HCC development Antibiotic treatment or lowering DCA levels decreased HCC development HFD mice showed enhanced serum levels of DCA and increased levels of Clostridium genus bacteria |
| 40 | Mouse (C57BL6/N) | Hepa 1-6 (mouse hepatoma cell line) s.c. injection | - Probiotic oral administration - 16S rDNA shotgun-metagenome sequencing for microbial analysis | Probiotic administration reduced tumor size and slowed down tumor growth Probiotic administration is associated with increased levels of Prevotella and Oscilibacter |
| 45 | Mouse (C57BL/6J) | SZT+HFD | - 16S rDNA gene Pyrosequencing | Atopobium spp., Bacteroides spp., Bacteroides vulgatus, Bacteroides acidifaciens, Bacteroides uniforms, Clostridium cocleatum, Clostridium xylanolyticum and Desulfovibrio spp. increased in NASH-HCC mice |
| 46 | Mouse (C57BL/6J) | SZT+HFD HFD | - BAs levels quantification in plasma, liver and feces - cholestyramine treatment - 16S rDNA gene Pyrosequencing | Total liver BAs were highest in the HCC stage More than HFD alone long-term fed mice developed HCC and showed increased liver and plasma BAs levels Liver and plasma BAs levels correlated with gut microbiota alterations Cholestyramine administration significantly reduced the incidence and size of HCC |
HCC: hepatocellular carcinoma; TLR: toll-like receptor; DEN: diethylnitrosamine; AFB: alfatoxin; DSS: dextran sulfate sodium; CCl4: carbon tetrachloride; CD: choline-deficient diet; LPS: lipopolysaccharide; WT: wild type; DMBA: dimethylbenz(a)anthracene; HFD: high-fat diet; DCA: deoxycholic acid; SZT: streptozotocin; BA: bile acid; LCA: lithocholic acid; TDCA: taurochenodeoxycholic acid PCR: polymerase chain reaction; rRNA: ribosomal RNA; rDNA: ribosomal DNA; s.c.: subcutaneous; TNFR1: tumor necrosis factor receptor 1; IL-1R1: interleukin 1 receptor type 1.